N-alkyl phenylcarboxamide beta-secretase inhibitors for the treatment of Alzheimer&#39;s disease

ABSTRACT

The present invention is directed to compounds which are inhibitors of the beta-secretase enzyme and which are useful in the treatment or prevention of diseases in which the beta-secretase enzyme is involved, such as Alzheimer&#39;s disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) fromProvisional Application No. 60/483,992, filed Jun. 30, 2003.

BACKGROUND OF THE INVENTION

Alzheimer's disease is characterized by the abnormal deposition ofamyloid in the brain in the form of extra-cellular plaques andintra-cellular neurofibrillary tangles. The rate of amyloid accumulationis a combination of the rates of formation, aggregation and egress fromthe brain. It is generally accepted that the main constituent of amyloidplaques is the 4 kD amyloid protein (βA4, also referred to as Aβ,β-protein and βAP) which is a proteolytic product of a precursor proteinof much larger size. The amyloid precursor protein (APP or AβPP) has areceptor-like structure with a large ectodomain, a membrane spanningregion and a short cytoplasmic tail. The Aβ domain encompasses parts ofboth extra-cellular and transmembrane domains of APP, thus its releaseimplies the existence of two distinct proteolytic events to generate itsNH₂— and COOH-termini. At least two secretory mechanisms exist whichrelease APP from the membrane and generate soluble, COOH-truncated formsof APP (APP_(S)). Proteases that release APP and its fragments from themembrane are termed “secretases.” Most APP_(S) is released by a putativeα-secretase which cleaves within the Aβ protein to release α-APP_(S) andprecludes the release of intact Aβ. A minor portion of APP_(S) isreleased by a β-secretase, which cleaves near the NH₂-terminus of Aβ andproduces COOH-terminal fragments (CTFs) which contain the whole Aβdomain.

Thus, the activity of β-secretase, or β-site amyloid precursorprotein-cleaving enzyme (“BACE”), leads to the abnormal cleavage of APP,production Aβ, and accumulation of β amyloid plaques in the brain, whichis a characteristic of Alzheimer's disease (see R. N. Rosenberg, Arch.Neurol., vol. 59, September 2002, pp. 1367-1368; H. Fukumoto et al,Arch. Neurol., vol. 59, September 2002, pp. 1381-1389; J. T. Huse et al,J. Biol. Chem., vol 277, No. 18, issue of May 3, 2002, pp. 16278-16284;K. C. Chen and W. J. Howe, Biochem. Biophys. Res. Comm, vol. 292, pp702-708, 2002). Therefore, therapeutic agents that can inhibitβ-secretase or BACE may be useful for the treatment of Alzheimer'sdisease.

The compounds of the present invention are useful for treatingAlzheimer's disease by inhibiting the activity of the β-secretase orBACE, thus preventing the formation of insoluble Aβ and arresting theproduction of Aβ.

SUMMARY OF THE INVENTION

The present invention is directed to compounds that are inhibitors ofthe β-secretase enzyme and BACE and which are useful in the treatment ofdiseases in which the β-secretase enzyme is involved, such asAlzheimer's disease. The invention is also directed to pharmaceuticalcompositions comprising these compounds and the use of these compoundsand compositions in the prevention or treatment of such diseases inwhich the β-secretase enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   R¹ is selected from the group consisting of:    -   (1) C₁₋₆alkyl, unsubstituted or substituted with —OR⁵ or        —S(O)₂—C₁₋₆alkyl,    -   (2) hydrogen,    -   (3) phenyl, and    -   (4) benzyl;-   R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) R⁴—S(O)_(p)—,        -   wherein R⁴ is independently selected from the group            consisting of:            -   (a) C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro,            -   (b) phenyl, and            -   (c) benzyl,    -   (3) R⁴—S(O)_(p)N(R⁵)—,        -   wherein R⁵ is independently selected from the group            consisting of:            -   (a) hydrogen,            -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 fluoro,            -   (c) —C₃₋₆cycloalkyl which is unsubstituted or                substituted with methyl,            -   (d) phenyl, which is unsubstitued or substituted with                halo or methoxy, and            -   (e) benzyl,    -   (4) —CN,    -   (5) —C₁₋₆alkyl-CN,    -   (6) halogen,    -   (7)

-   -   -   wherein R^(8a) and R^(8b) are independently selected from            the group consisting of:            -   (a) hydrogen,            -   (b) —CN,            -   (c) halo,            -   (d) —C₁₋₆alkyl,            -   (e) —O—R⁵,            -   (f) —S—R⁵,            -   (g) —CO₂R⁵, and            -   (h) tetrazolyl,

    -   (8)

-   -   -   wherein n is 1, 2, 3 or 4;

-   R³ is selected from the group consisting of:

-   R^(6a), R^(6b), and R^(6c) are independently selected from the group    consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —OR⁵,    -   (4) —SR⁵, and    -   (5) —C₁₋₆alkyl;-   R⁷ is selected from the group consisting of a bond, —CH═CH—, —O—,    —S—, and —NH—;-   R⁹ and R¹⁰ are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, unsubstituted or substituted with —CN or 1-4        halo,    -   (3) —C₃₋₆cycloalkyl,    -   (4) phenyl, which is unsubstitued or substituted with halo or        methoxy, and    -   (5) benzyl,    -   or R⁹ and R¹⁰ may be joined together to form a pyrrolidine or        piperidine ring which is unsubstituted or substituted with        benzyl, —OR⁵ or 1-4 halo;-   m is independently 0, 1, or 2;-   p is independently 0, 1, or 2,    and pharmaceutically acceptable salts thereof.

An embodiment of the present invention includes compounds wherein R¹ isC₁₋₆alkyl.

Another embodiment of the present invention includes compounds whereinR¹ is methyl.

Another embodiment of the present invention includes compounds whereinR¹ is ethyl.

Another embodiment of the present invention includes compounds whereinR² is:R⁴—S(O)₂—NR⁵—and wherein R⁴ is selected from the group consisting of:

-   -   (1) C₁₋₆alkyl,    -   (2) phenyl, and    -   (3) benzyl;

-   R⁵ is selected from the group consisting of:    -   (1) C₁₋₆alkyl,    -   (2) phenyl,    -   (3) benzyl, and    -   (4) hydrogen.

Another embodiment of the present invention includes compounds whereinR³ is:

and wherein R⁵ is methyl, R^(6a) is H or F, R^(6b) and R^(6c) arehydrogen.

Another embodiment of the present invention includes compounds whereinR³ is:

Another embodiment of the present invention includes compounds whereinR⁹ is hydrogen.

Another embodiment of the present invention includes compounds whereinR¹⁰ is C₁₋₆alkyl.

Another embodiment of the present invention includes compounds whereinR¹⁰ is iso-butyl.

Another embodiment of the present invention includes a compound which isselected from the title compounds of the following Examples andpharmaceutically acceptable salts thereof.

The compounds of the instant invention have at least one asymmetriccenter. Additional asymmetric centers may be present depending upon thenature of the various substituents on the molecule. Compounds withasymetric centers give rise to enantiomers (optical isomers),diastereomers (configurational isomers) or both, and it is intended thatall of the possible enantiomers and diastereomers in mixtures and aspure or partially purified compounds are included within the scope ofthis invention. The present invention is meant to encompass all suchisomeric forms of these compounds.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The compounds of the present invention are prepared by the methodsoutlined in Scheme 1.

Referring to Scheme 1, N-Boc protected amino acids (1—A) are reactedwith primary or secondary amines in the presence of a coupling agentsuch as BOP reagent and an amine base to afford an N-protected aminoamide (1—B). The Boc group is removed under acidic conditions such asHCl gas in ethyl acetate. The resulting amino acid amide salt (1—C) isreductively aminated with boc protected phenylalanine aldehyde using areducing agent such as sodium cyanoborohydride in methanol. The product(1-D) is treated with a strong acid such as HCl gas or trifluoroaceticacid to remove the t-butyloxycarbonyl protecting group to provide theintermediate diamine salt (1-E). Compounds 1-E are coupled to benzoicacid derivatives by standard amide coupling procedures such as BOPreagent and a trialkylamine base to provide final compounds (I).

Scheme 2 illustrates an alternative process for the synthesis ofinhibitors (I). Boc-Phe is reduced by standard methods to afford thecorresponding alcohol (2-B). The resulting alcohol is activated forazide displacement by treatment with methanesulfonyl chloride and anamine base such as triethylamine. Azide formation takes place byreacting mesylate 2-C with an excess of sodium azide in a polar aproticsolvent such as DMF at an elevated temperature. The product (2-D) istreated with a strong acid such as HCl gas to remove thet-butyloxycarbonyl protecting group to provide the amino azide salt 2-E.Standard amide coupling of amine 2-E with a benzoic acid derivativeprovides 2-F. The azide functional group is reduced with a phosphinereagent to provide 2-G which is then alkylated with an appropriatelysubstituted bromoacetate ester and a base such as potassium carbonate.The ester 2-H is then saponified with a base such as lithium hydroxideto afford the corresponding carboxylic acid. Compounds 2-I are coupledto a benzoic acid derivative by standard amide coupling procedures suchas BOP reagent and a trialkylamine base to provide final compounds I.

A wide variety of benzoic acids are applicable to schemes 1 and 2 andinclude examples where R² is sulfonamide, sulfone, amide, nitrile,alkylnitrile, halogen, phenyl, and cyanocycloalkyl. R³ of the benzoicacid in Schemes 1 and 2 is generally selected from a carboxyaminobenzylgroup, a substituted olefin, an O or N alkylcyclopropyl, or an alkylether, alkylthioether, or secondary amine.

The term “substantially pure” means that the isolated material is atleast 90% pure, and preferably 95% pure, and even more preferably 99%pure as assayed by analytical techniques known in the art. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic salts, manganous, potassium,sodium, zinc, and the like. Particularly preferred are the ammonium,calcium, magnesium, potassium, and sodium salts. Salts in the solid formmay exist in more than one crystal structure, and may also be in theform of hydrates. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines, and basic ion exchange resins, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids.

The present invention is directed to the use of the compounds disclosedherein as inhibitors of β-secretase enzyme activity or β-site amyloidprecursor protein-cleaving enzyme (“BACE”) activity, in a patient orsubject such as a mammal in need of such inhibition, comprising theadministration of an effective amount of the compound. The terms“β-secretase enzyme,” “β-site amyloid precursor protein-cleavingenzyme,” and “BACE” are used interchangably in this specification. Inaddition to humans, a variety of other mammals can be treated accordingto the method of the present invention.

The present invention is further directed to a method for themanufacture of a medicament or a composition for inhibiting β-secretaseenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutical carrier or diluent.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk ofAlzheimer's disease, other diseases mediated by abnormal cleavage ofamyloid precursor protein (also referred to as APP), and otherconditions that may be treated or prevented by inhibition ofβ-secretase. Such conditions include mild cognitive impairment, Trisomy21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type(HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophiclateral sclerosis, progressive supranuclear palsy, head trauma, stroke,Down syndrome, pancreatitis, inclusion body myositis, other peripheralamyloidoses, diabetes and atherosclerosis.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whominhibition of β-secretase enzyme activity is desired, but may alsoencompass other mammals, such as dogs, cats, mice, rats, cattle, horses,sheep, rabbits, monkeys, chimpanzees or other apes or primates, forwhich inhibition of β-secretase enzyme activity or treatment of theabove noted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichthe compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

Examples of combinations of the compounds of the present invention withother drugs in either unit dose or kit form include combinations with:anti-Alzheimer's agents, for example other beta-secretase inhibitors orgamma-secretase inhibitors; HMG-CoA reductase inhibitors; NSAID'sincluding ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptorantagonists or CB-1 receptor inverse agonists; antibiotics such asdoxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptorantagonists, such as memantine; cholinesterase inhibitors such asgalantamine, rivastigmine, donepezil and tacrine; or other drugs thataffect receptors or enzymes that either increase the efficacy, safety,convenience, or reduce unwanted side effects or toxicity of thecompounds of the present invention. The foregoing list of combinationsis illustrative only and not intended to be limiting in any way.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients. In general, pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, granulating and disintegrating agents, binding agents andlubricating agents. The tablets may be uncoated or they may be coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent or assoft gelatin capsules wherein the active ingredient is mixed with wateror an oil medium.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents and dispersing or wetting agents.The aqueous suspensions may also contain one or more preservatives,coloring agents, flavoring agents, and sweetening agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil or in a mineral oil. The oily suspensions may containa thickening agent. Sweetening agents and flavoring agents may be addedto provide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Additional excipients, for example sweetening,flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions, which may also contain excipients such assweetening and flavoring agents.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oleagenous suspension, which may be formulatedaccording to the known art, or may be administered in the form ofsuppositories for rectal administration of the drug.

The compounds of the present invention may also be administered byinhalation, by way of inhalation devices known to those skilled in theart, or transdermally by way of transdermal patch.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individuals body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology or the diseased (i.e., reversing thepathology and/or symptomatology). The term “controlling” includespreventing, treating, eradicating, ameliorating or otherwise reducingthe severity of the condition being controlled.

The compositions containing compounds of the present invention mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. The term “unit dosageform” is taken to mean a single dose wherein all active and inactiveingredients are combined in a suitable system, such that the patient orperson adminstering the drug to the patient can open a single containeror package with the entire dose contained therein, and does not have tomix any components together from two or more containers or packages.Typical examples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples in thepharmacy arts of unit dosage forms.

The compositions containing compounds of the present invention mayconveniently be presented as a kit, whereby two or more components,which may be active or inactive ingredients, carriers, diluents, and thelike, are provided with instructions for preparation of the actualdosage form by the patient or person adminstering the drug to thepatient. Such kits may be provided with all necessary materials andingredients contained therein, or they may contain instructions forusing or making materials or components that must be obtainedindependently by the patient or person administering the drug to thepatient.

When treating, preventing, controlling, ameliorating, or reducing therisk of Alzheimer's disease or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 milligram to about 100 milligram perkilogram of animal body weight, preferably given as a single daily doseor in divided doses two to six times a day, or in sustained releaseform. The total daily dosage is from about 1.0 milligrams to about 2000milligrams, preferably from about 0.1 milligrams to about 20 milligramsper kilogram of body weight. In the case of a 70 kg adult human, thetotal daily dose will generally be from about 7 milligrams to about1,400 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day.

Specific dosages of the compounds of the present invention, orpharmaceutically acceptable salts thereof, for administration include 1mg, 5 mg, 10 mg, 30 mg, 80 mg, 100 mg, 150 mg, 300 mg and 500 mg.Pharmaceutical compositions of the present invention may be provided ina formulation comprising about 0.5 mg to 1000 mg active ingredient, morepreferably comprising about 0.5 mg to 500 mg active ingredient or 0.5 mgto 250 mg active ingredient, or 1 mg to 100 mg active ingredient.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The utility of the compounds in accordance with the present invention asinhibitors of β-secretase enzyme activity may be demonstrated bymethodology known in the art. Enzyme inhibition is determined asfollows.

FRET Assay: A homogeneous end point fluorescence resonance energytransfer (FRET) assay is employed with the substrate([TAMRA-5-CO-EEISEVNLDAEF-NHQSY]QFRET), which is cleaved by BACE 1 torelease the fluorescence from TAMRA. The Km of the substrate is notdetermined due to the limit of solubility of the substrate. A typicalreaction contains approximately 30 nM enzyme, 1.25 μM of the substrate,and buffer (50 mM NaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTAand 1 mM deferoxamine) in a total reaction volume of 100 μl. Thereaction is proceeded for 30 min and the liberation of TAMRA fragment ismeasured in a 96-well plate LJL Analyst AD using an excitationwavelength of 530 nm and an emission wavelength of 580 nm. Under theseconditions, less than 10% of substrate is processed by BACE 1. Theenzyme used in these studies was soluble (transmembrane domain andcytoplasmic extension excluded) human protein produced in a baculovirusexpression system. To measure the inhibitory potency of compounds,solutions of inhibitor in DMSO (four concentrations of the inhibitorswere prepared: 1 mM, 100 μM, 10 μM, 1 μM) were included in the reactionsmixture (final DMSO concentration is 0.8%). All experiments wereconducted at room temperature using the standard reaction conditionsdescribed above. To determine the IC₅₀ of the compound, competitiveequation V0/Vi=1+[I]/[IC50] was used to predict the inhibitory potencyof the compounds. The errors in reproducing the dissociation constantsare typically less than two-fold.

HPLC assay: A homogeneous end point HPLC assay is employed with thesubstrate (coumarin-CO-REVNFEVEFR), which is cleaved by BACE 1 torelease the N-terminal fragment attached with coumarin. The Km of thesubstrate is greater than 100 μM and can not be determined due to thelimit of solubility of the substrate. A typical reaction containsapproximately 2 nM enzyme, 1.0 μM of the substrate, and buffer (50 mMNaOAc, pH 4.5, 0.1 mg/ml BSA, 0.2% CHAPS, 15 mM EDTA and 1 mMdeferoxamine) in a total reaction volume of 100 μl. The reaction isproceeded for 30 min and the reaction is stopped by the addition of 25μL of 1 M Tris-HCl, pH 8.0. The resulting reaction mixture was loaded onthe HPLC and the product was separated from substrate with 5 min lineargradient. Under these conditions, less than 10% of substrate isprocessed by BACE 1. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system. To measure the inhibitorypotency for compounds, solutions of inhibitor in DMSO (12 concentrationsof the inhibitors were prepared and the concentration rage was dependenton the potency predicted by FRET) were included in the reaction mixture(final DMSO concentration is 10%). All experiments were conducted atroom temperature using the standard reaction conditions described above.To determine the IC₅₀ of the compound, four parameters equation isemployed for curve fitting. The errors in reproducing the dissociationconstants are typically less than two-fold.

In particular, the compounds of the following examples had activity ininhibiting the beta-secretase enzyme in the aforementioned assay,generally with an IC₅₀ from about 1 nM to 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors the beta-secretase enzyme activity.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following examples are provided so that the invention mightbe more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Intermediate I

Step A: To a solution containing 2.0 g (10.0 mmol) of(S)—N-Boc-aminobutyric acid in 50 mL of DCM was added 730 mg (10.0 mmol)of isobutyl amine, 4.42 g (10.0 mmol) of BOP Reagent and 4.2 mL (24.0mmol) of Hunig's base. The reaction mixture was stirred at rt for 30 minbefore it was extracted with 10% citric acid (10 mL), water (10 mL),saturated NaHCO₃ (10 mL) and brine (10 mL). The organic phase was driedover MgSO₄, concentrated and chromatographed (1:1 EtOAc/Hexanes) toafford 2.4 g of the desired amide. ¹H NMR δ 6.11 (bs, 1H), 4.96 (bs,1H), 3.97 (m, 1H), 3.08 (m, 2H), 1.88 (m, 1H), 1.80 (m, 1H), 1.66 (m,1H), 1.45 (s, 9H), 0.95 (m, 9H). LCMS (M+H)=259.27

Step B: A 0° C. solution containing 1.58 g (6.10 mmol) of Boc amide Awas dissolved in 40 mL of EtOAc and 4 ml of MeOH and saturated with HClgas for 10 minutes. The reaction mixture was stirred for 1 h thenconcentrated to a semi-solid. The residue was triturated with 50 mL ofether to afford 1.10 g of the amine HCl salt as an extremely hygroscopicsolid. ¹H NMR (CD³OD) δ 3.78 (t, J=7.8 Hz, 1H), 3.18 (m, 2H), 1.85 (m,3H), 1.01 (t, J=7.8 Hz, 3H), 0.87 (d, 6H). LCMS (M+H)=159.31

Step C: To a solution containing 200 mg (0.76 mmol) of (S)—N-Boc-Phe-CHOin 5 mL of MeOH was added 746 mg (3.81 mmol, 5 equiv) of amine B and47.0 mg (0.76 mmol) of NaBH₃CN. The resulting solution was stirred at rtover 16 h. The solvent was removed and the residue was dissolved in 25mL of DCM and washed with NaHCO₃ (10 mL) and brine (10 mL). Evaporationof the solvent and chromatography (EtOAc) left 245 mg of the desiredproduct that was used directly in the next reaction. ¹H NMR (CDCl₃) δ7.4-7.1 (m, 5H), 4.84 (d, J=2.4 Hz, 1H), 4.11 (bs, 1H), 3.60 (bs, 1H),3.11 (m, 4H), 2.82 (m, 4H), 1.81 (m, 4H), 1.43 (s, 9H), 0.99 (t, J=7.8Hz, 3H), 0.82 (d, J=7.7 Hz, 6H).

Step D: A 0° C. solution containing 201 mg (0.5 mmol) of Boc amine fromstep C was dissolved in 25 mL of EtOAc and saturated with HCl gas for 5minutes. The reaction mixture was stirred for 1 h, concentrated andtriturated with ether to afford 185 mg of compound I as a white solid.¹H NMR (CD3OD) δ 7.44-7.15 (m, 5H), 3.83 (m, 1H), 3.33 (m, 1H), 3.18 (m,1H), 3.06 (m, 4H), 2.00 (m, 2H), 1.77 (m, 1H), 1.01 (t, J=7.8 Hz, 3H),0.88 (d, J=7.8 Hz, 6H).

Intermediate II

Prepared similar to Intermediate I but substituting(S)—N-Boc-aminopentanoic acid as the amine in step A. ¹H NMR (CD₃OD) δ8.55 (bt, 1H), 7.41-7.26 (m, 5H), 3.92 (t, J=6.8 Hz, 2H), 3.77 (dd, 2H),3.30 (d, J=1.7 Hz, 1H), 3.08 (dd, J=13.5, 1.7 Hz, 1H), 3.03-2.95 (m,4H), 1.88 (m, 2H), 1.77 (m, 1H), 1.41 (m, 2H), 0.94 (t, J=7.4 Hz, 3H),0.90 (d, J=6.8 Hz, 6H)

Intermediate III

Prepared similar to Intermediate I but substituting (S)—N-Boc-methioninesulfone as the amine in step A. ¹H NMR (CD₃OD) δ 8.42 (bs, 1H),7.44-7.25 (m, 5H), 4.02 (m, 1H), 3.83 (m, 1H), 3.38-3.05 (m, 7H), 3.00(s, 3H), 2.39 (bd, 2H), 1.77 (m, 1H), 0.92 (d, J=6.7 Hz, 6H).

Intermediate IV

Prepared similar to Intermediate I but substituting (S)—N-Boc-alanine asthe amine in step A. ¹H NMR (CD₃OD) δ 8.41 (bt, 1H), 7.41-7.26 (m, 5H),4.02 (m, 1H), 3.81 (m, 2H), 3.40-3.00 (m, 5H), 1.80 (m, 2H), 1.61 (d,J=6.7 Hz, 3H), 0.97 (d, J=6.8 Hz, 6H)

Intermediate V

Prepared similar to Intermediate I but substituting (S)—N-Boc-homoserineas the amine in step A. ¹H NMR (CD₃OD):. δ 7.37-7.27 (m, 5H), 4.13 (m,1H), 3.99 (m, 1H), 3.86-3.75 (m, 2H), 3.38-3.25 (m, 2H), 3.03 (m, 2H),2.89 (m 1H), 2.76 (d, J=7.14 Hz, 2H), 2.14 (m, 1H), 1.99 (m, 1H), 1.01(d, J=6.68 Hz, 6H). LCMS (M+H)=308.1

EXAMPLE 1

Step A. To a stirred slurry of dimethyl 5-aminoisophthalate (5.0 g,23.90 mmol) in 100 mL CH₂Cl₂/Pyridine (3:1) at 0° C. was addedmethanesulfonyl chloride (1.85 mL, 23.90 mmol). The resulting mixturewas stirred for 4 h at room temperature. The solvent was removed invacuo and ethyl acetate (100 mL) was added resulting in precipitateformation. The product was collected by filtration to give 5.14 g of thesulfonamide as a white solid. ¹H NMR (DMSO_(d6)) δ 8.15 (s, 1H), 8.02(s, 2H), 3.89 (s, 6H), 3.02 (s, 3H). LCMS [M−OCH₃]⁺=256.16

Step B. To a solution of sodium hydride (0153 g, 3.83 mmol, 60% oildispersion) in 10 mL DMF was added sulfonamide (1.0 g, 3.48 mmol) fromstep A followed by methyl iodide (0.43 mL, 6.97 mmol). After 1 hr thereaction was quenched with H₂O (100 mL) and extracted with EtOAc (3×50mL). The organic extracts were dried over MgSO₄ and evaporated to give1.03 g of N-methylsulfonamide. ¹H NMR (DMSO_(d6)) δ 8.40 (s, 1H), 8.19(s, 2H), 3.91 (s, 6H), 3.34 (s, 3H), 3.01 (s, 3H). LCMS [M+H]=302.15

Step C. Diester (1.03 g, 3.38 mmol) from step B was dissolved in 50 mLTHF: MeOH (1:1) and cooled to 0° C. 1N NaOH (3.38 mL, 3.38 mmol) wasadded and the reaction was allowed to warm to RT over 8 hours. Thesolution was acidified with 1N HCl (30 mL) and extracted with EtOAc(3×50 mL). The combined organic extracts were washed with brine anddried over MgSO₄, filtered and concentrated in vacuo. Purification onsilica gel (5% MeOH/CHCl₃ containing 1% HOAc) gave 795 mg (82%) of themono acid. ¹H NMR (DMSO_(d6)) δ 8.30 (s, 1H), 8.10 (s, 2H), 3.84 (s,3H), 3.27 (s, 3H), 2.94 (s, 3H). LCMS (M+H)=288.16

Step D. A solution containing 133 mg (0.46 mmol) of the monoacid fromstep C in 5 mL CH₂Cl₂, BOP reagent (0.235 g, 0.55 mmol), (R)—(+)-4-fluoro-methylbenzylamine (76 mg, 0.55 mmol), anddiisopropylethylamine (0.24 mL, 1.39 mmol) was stirred at ambienttemperature for 1 h. Evaporation of the solvent and columnchromatography on silica gel (90% EtOAc/Hexanes) afforded 71 mg of thebenzyl amide. LCMS (M+H)=409.27

Step E. To 179 mg (0.438 mmol) of the benzyl amide from step D in 10 mLTHF:MeOH (1:1) was added 2 N NaOH (0.66 mL, 1.32 mmol). The solution washeated to 50° C. for 1 h. After cooling the solution was acidified bythe addition of 1 N HCl (20 mL) and extracted with EtOAc (3×30 mL). Thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo to yield 173 g of the desired carboxylic acid. ¹HNMR (CDCl₃) δ 8.22 (t, 1H), 8.11 (m, 1H), 8.06 (m, 1H), 7.34 (m, 5H),6.47 (d, J=7.1 Hz, 1H), 5.33 (m, 1H), 3.37 (s, 3H), 2.87 (s, 3H), 1.64(d, J=7.0 Hz, 3H). LCMS (M+H)=395.2

Step F. To a solution containing 39.5 mg (0.10 mmol) of the carboxylicacid from step E in 5 mL of DCM was added intermediate aminedihydrochloride IV (35.7 mg, 0.10 mmol), 44.2 mg (0.10 mmol) of BOPreagent and 0.076 mL (0.44 mmol) of diisopropylethyl amine. The reactionmixture was stirred at rt for 1 h then extracted with 2×1 mL 1N HCl, 2×1mL water, and 1 mL brine. The organic phase was dried over MgSO₄ andsubjected to reverse phase chromatography to afford 57.7 mg of thedesired product as a white solid. 1H NMR (CD₃OD) δ 9.03 (d, J=7.69 Hz,1H), 8.90 (bs, 1H), 8.61 (d, J=8.42 Hz, 1H), 8.45 (m, 1H), 8.23 (s, 1H),8.03 (s, 1H), 7.92 (s, 1H), 7.44 (m, 2H), 7.29-7.14 (m, 7H), 5.19 (m,1H), 4.51 (bs, 1H), 3.86 (m, 1H), 3.30 (s, 3H), 3.10 (bs, 1H), 3.00 (s,3H), 2.99-2.87 (m, 4H), 1.68 (m, 1H), 1.50 (d, J=7.15 Hz, 3H), 1.40 (d,J=6.77 Hz, 3H). LCMS (M+H)=654.28.

EXAMPLE 2

Step A: To 3-amino-5-nitrobenzoic acid (3.60 g, 19.78 mmol) in 100 mLMeOH was added thionyl chloride (2,59 g, 21.76 mmol). The solution washeated to 65° C. for 12 h. Concentration in vacuo afforded the 4.57 g ofthe methyl ester hydrochloride salt. ¹H NMR (CD₃OD) δ 8.62 (s, 1H), 8.28(s, 1H), 8.19 (s, 1H), 3.99 (s, 3H).

Step B: To a solution of 3.53 g (18.0 mmol) amino ester from step A in100 mL CH₂Cl₂/pyridine (3:1) was added methanesulfonyl chloride (2.07 g,18.0 mmol). The reaction was stirred at ambient temperature for 1 hfollowed by evaporation of the solvent. The gummy residue was taken upin EtOAc (100 mL), acidified with 1N HCl (100 mL), and extracted withEtOAc (3×100 mL). The combined organic extracts were dried over MgSO₄,filtered, and concentrated in vacuo to provide 3.97 of the sulfonamideas an off-white solid. ¹H NMR (CD₃OD) δ 8.46 (s, 1H), 8.30 (s, 1H), 8.18(s, 1H), 3.97 (s, 3H), 3.09 (s, 3H).

Step C: Sodium Hydride (0.26 g, 6.55 mmol, 60% oil dispersion) wassuspended in 10 mL DMF to which 1.5 g (5.45 mmol) of the sulfonamidefrom step B in 10 mL DMF was added followed by 0.93 g (6.55 mL) methyliodide. The solution was stirred at ambient temperature for 3 h. Thereaction was quenched with H₂O (250 mL), extracted with EtOAc (3×200mL), dried over MgSO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography provided 1.43 g of the N-methylsulfonamide. LCMS (M-H₂O)=272.2

Step D. To a solution of the nitro sulfonamide (2.7 g, mmol) from step Cand 0.15 g of 10% Pd/C in 50 mL EtOH containing HOAc (2 mL) was stirredat room temperature under a balloon of hydrogen gas for 12 h. Themixture was filtered through a pad of Celite, concentrated, and purifiedon silica gel (100% EtOAc) to afford 2.05 g of the desired aniline. ¹HNMR (CD₃OD) δ 7.29 (s, 1H), 7.26 (s, 1H), 6.95 (s, 1H), 3.87 (s, 3H),3.27 (sm 3H), 2.89 (s, 3H). LCMS (M+H)=258.2

Step E. A solution containing 0.32 g (1.3 mmol) of the aniline from stepD, 0.33 g (2.5 mmol) of 1-bromo-2-butyne, and 0.35 g (2.5 mmol) K₂CO₃ in12.5 mL of acetonitrile was heated at reflux for 4 h The reactionmixture was cooled and diluted with 60 mL of H₂O. The mixture wasextracted with of EtOAc (3×60 mL). The combined organics were washedwith brine (60 mL) then dried (MgSO₄). The solvent was removed in vacuoand purified by silica gel chromatography (20%-50% EtOAc:Hex) to afford160.0 mg of alkynyl aniline. LCMS (M+H)=311.2

Step F. A solution containing 83 mg (0.27 mmol) of alkynyl aniline fromstep E in 3 mL MeOH was treated with a catalytic amount of Lindlar'scatalyst and stirred at room temperature under a hydrogen atmosphere for10 min. The reaction was filtered through plug of silica gel and thesolvent was removed in vacuo. Purification by reverse phase HPLCafforded 38 mg of Z-alkenyl aniline. LCMS (M+H)=313.2

Step G. A solution containing 38 mg (0.12 mmol) Z-alkenyl aniline fromstep F in 2.5 mL EtOAc at 0° C. was treated with 58 mg (1.3 mmol) offreshly prepared diazomethane and a catalytic amount of palladiumacetate and stirred at 0° C. for 15 min. The reaction was filteredthrough a plug of silica gel. Evaporation of the solvent left 34.0 mg ofthe methyl cyclopropyl methyl aniline. LCMS (M+H)=327.2

Step H. To 34 mg (0.10 mmol) of the methyl cyclopropyl methyl anilinefrom step G in 5 mL THF:MeOH (1:1) was added 2 N NaOH (0.15 mL, 0.30mmol). The solution was heated to 50° C. for 1 h. After cooling thesolution was acidified by the addition of 1 N HCl (20 mL) and extractedwith EtOAc (3×30 mL). The combined organic extracts were dried overMgSO₄, filtered, and concentrated in vacuo to yield 0.020 g of thedesired carboxylic acid. LCMS (M+H)=313.2

Step I. A solution containing 31.3 mg (0.10 mmol) of the carboxylic acidfrom step H, 37.6 mg (0.1 mmol) of intermediate diamine II, 44.4 mg (0.1mmol) of BOP reagent and 0.076 mL (0.44 mmol) of Hunig's base werestirred at rt for 1 h in 5 mL of DCM. The solvent was evaporated and theresidue was purified by reverse phase chromatography to afford 35 mg ofthe title compound as a white solid. ¹H NMR (CD₃OD) δ 7.32-6.98 (m, 8H),4.59 (m, 1H), 4.14-4.07 (m, 1H), 3.84 (m 1H), 3.36 (s, 3H), 3.33 (m,2H), 3.31 (s, 3H), 3.24-3.07 (m, 2H), 3.01 (m, 2H), 2.92 (m, 3H), 2.03(m, 2H), 1.87-1.63 (m, 4H), 1.25 (m, 1H), 1.07 (m, 2H), 0.97 (m, 3H),0.92 (d, J=6.6 Hz, 6H), 0.83-0.76 (m, 1H). LCMS (M+H)=600.32

EXAMPLE 3

Step A: 3-Nitrobenzoate (35.3 g, 195 mmol) in triflic acid (100 mL) at0° C. was added NIS (43.8 g, 195 mmol) in ten portions. Remove ice bathand stir for 48 hrs. The reaction typically goes to 50% completion. Atthis time more NIS could be added or cool to 0° C. and quench withcareful dropwise addition of water. The mixture was extracted threetimes with EtOAc (250 mL) and the combined extracts were washed with a10% NaHSO₃ solution, followed by water. The organics were dried overNa₂SO₄, concentrated, and purified on silica gel (10% EtOAc in Hex)affording 24.1 g.

Step B: Tin chloride (88.6 g, 392 mmol) in EtOH (50 mL) was refluxed andthe nitrobenzoate from step A (24.1 g, 78.4 mmol) in 1:1 THF:EtOH (100mL) was added dropwise. The reaction mixture was refluxed for 30 minutesthen cooled to 0° C. The resulting solution was basified to pH 8-9 withaq. Na₂CO₃. The aqueous layer was extracted three times with EtOAc (700mL) and the combined extracts were washed with saturated NaHCO₃ thenbrine. The organics were dried over Na₂SO₄ and concentrated to afford21.7 g of the crude aniline which was used without further purification.

Step C: To a 0° C. solution of aniline from step B (21.7 g, 78.3 mmol)in 3:1 CH₂Cl₂:pyridine (75 mL) was added methanesulfonyl chloride (6.36mL, 82.2 mmol). The ice bath was removed after 15 minutes and thesolution was stirred overnight at room temperature. The reaction mixturewas extracted several times with 1N HCl. The organic phase was dried,concentrated, and chromatographed (1:1 EtOAc:Hex) to afford 25.2 g ofthe desired sulfonamide as a white solid.

Step D: The sulfonamide from step C (23.6 g, 66.5 mmol) in DMF (75 mL)at 0° C. was treated with 60% NaH (2.92 g, 73.1 mmol). The solutionstirred for 30 minutes before MeI (4.55 mL, 73.1 mmol) was added. Theice bath was removed and the solution was stirred at rt for twelvehours. The reaction was quenched with saturated NH₄Cl solution andextracted three times with EtOAc (150 mL). The combined organic werewashed with water (5×50 mL), dried, concentrated to afford 25.3 g of thedesired methylated anilide which was used without further purification.

Step E: Trans-2-methylcyclopropanemethanol (7.0 g, 81 mmol) was added toa solution of PCC (28 g, 130 mmol) in CH₂Cl₂ (225 mL). The solutionbecame black and was stirred for three hours at room temperature. Thereaction mixture was diluted with ether (250 mL) and decanted. Theliquid solution was filtered through a 4 inch plug of Florisil and thesolvent was removed by distillation through a Vigreux column to afford10 g of the desired aldehyde.

Step F: To a solution of PPh₃ (12.4 g, 47.5 mmol) in CH₂Cl₂ (100 mL) at0° C. was added CBr₄ (7.88 g, 23.7 mmol). The reaction mixture wasstirred for 10 minutes then treated with the carboxaldehyde from step E(1.0 g, 12 mmol). The solution was stirred for 30 minutes at 0° C. then1 hr at room temperature. Hexane was added and the solids were filtered,and the filtrate was concentrated to afford 4.4 g of the dibromide.

Step G: The dibromide from step F (15.4 g, 64.1 mmol) in 60 mL ofcyclohexane at −78° C. was treated with 2.0 M n-BuLi in cyclohexane(64.1 mL, 128 mmol). The resulting reaction mixture was stirred at −78°C. for 1 hr then warmed to room temperature where it was stirred for 2hr. The reaction was quenched with water and extract with cyclohexane(3×25 mL). The product was purified by distillation (bp=69-72 C).

Step H: A 100 mL 3-neck round bottom flask was charged with InCl₃ (0.829g, 10.4 mmol) and dried under vacuum with a heat gun for 2 minutes. THF(16 mL) was added under nitrogen and the flask was immersed in a −78° C.ice bath. DIBAL-H (12.4 mL, 1M in hexanes) was then added dropwise andthe resulting solution was stirred for 30 minutes at −78° C. After thistime, the acetylene from step G (10.4 mmol) was added followed by 1.0 MEt₃B (1.6 mL, 1M in hexanes). This reaction mixture was stirred at −78°C. for 2.5 hr then warmed to room temperature. DMI (12 mL) andaryliodide from step D (1.47 g, 4.0 mmol) was added followed by apalladium trifurylphosphine complex [prepared from Pd₂(DBA)₃° CHCl₃ (20mg) and trifurylphosphine (28 mg) in THF (6 mL)]. The resulting reactionmixture was heated at 60° C. for 2 hr, quenched with water and extractedwith ether (3×50 mL). The combined organic extracts were dried, andconcentrated and the product was purified on a chiral OJ column (60:40Hexane w/0.1% TFA:EtOH). Collection of the first peak afforded 276 mg ofthe desired diastereomer.

Step I: To 276 mg (0.853 mmol) of the ester from step H in 10 mLTHF:MeOH:water (3:1:1) was added 2 N NaOH (0.64 mL, 1.28 mmol). Thesolution was stirred at rt for 2 h. The reaction mixture wasconcentrated and acidified with 2 N HCl (10 mL) and extracted with CHCl₃(3×20 mL). The combined organic extracts were dried over MgSO₄,filtered, and concentrated to yield 253 mg of the desired carboxylicacid. LCMS (M+H)=310.12

Step J: A solution containing 8.0 mg (0.026 mmol) of the carboxylic acidfrom step I, 10.6 mg (0.031 mmol) of intermediate diamine IV, 11.4 mg(0.026 mmol) of BOP reagent and 0.026 mL (0.11 mmol) of Hunig's base wasstirred at rt for 1 h in 3 mL of DCM. The solvent was evaporated and theresidue was purified by reverse phase chromatography to afford 17.6 mgof the title compound as a white solid. 1H NMR (400 MHz, CDCl₃) δ 7.95(bd, H), 7.62-7.57 (m, 3H), 7.33-7.22 (m, 4H), 6.74 (s, 1H), 6.21 (d,1H), 5.15 (dt, 1H), 4.66 (m, 1H), 3.96 (bd, 1H), 3.48-3.39 (m, 4H),3.09-2.95 (m, 5H), 2.86 (s, 1H), 1.56-1.44 (m, 5H), 1. (m, 2H),1.12-1.11 (d, 3H), 0.92-0.84 (m, 7H), 0.66-0.62 (m, 2H). LCMS(M+H)=569.2

The following compounds were prepared in a manner similar to the titlecompounds of the foregoing examples using appropriate starting materialsand reagents.

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While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

1. A compound of the formula I:

wherein: R¹ is selected from the group consisting of: (1) C₁₋₆alkyl,unsubstituted or substituted with —OR⁵ or —S(O)₂—C₁₋₆alkyl, (2)hydrogen, (3) phenyl, and (4) benzyl; R² is selected from the groupconsisting of: (1) R⁴—S(O)_(p)—, wherein R⁴ is independently selectedfrom the group consisting of: (a) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 fluoro, (b) phenyl, and (c) benzyl, (2)R⁴—S(O)_(p)N(R⁵)—, wherein R⁵ is independently selected from the groupconsisting of: (a) hydrogen, (b) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 fluoro, (c) —C₃₋₆cycloalkyl which is unsubstitutedor substituted with methyl, (d) phenyl, which is unsubstitued orsubstituted with halo or methoxy, and (e) benzyl, (3) —CN, (4)—C₁₋₆alkyl-CN, (5) halogen, (6)

wherein R^(8a) and R^(8b) are independently selected from the groupconsisting of: (a) hydrogen, (b) —CN, (c) halo, (d) —C₁₋₆alkyl, (e)—O—R⁵, (f) —S—R⁵, (g) —CO₂R⁵, and (h) tetrazolyl, (7)

wherein n is 1, 2, 3 or 4; R³ is selected from the group consisting of:

R^(6a), R^(6b), and R^(6c) are independently selected from the groupconsisting of: (1)hydrogen, (2)halogen, (3) —OR⁵, (4) —SR⁵, and (5)—C₁₋₆alkyl; R⁷ is selected from the group consisting of a bond, —CH=CH—,—O—, —S—, and —NH—; R⁹ and R¹⁰are independently selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₆alkyl, unsubstituted or substitutedwith —CN or 1-4 halo, (3) —C₃₋₆cycloalkyl, (4) phenyl, which isunsubstitued or substituted with halo or methoxy, and (5) benzyl, or R⁹and R¹⁰ may be joined together to form a pyrrolidine or piperidine ringwhich is unsubstituted or substituted with benzyl, —OR⁵ or 1-4 halo; mis independently 0, 1, or 2; p is independently 0, 1, or 2, andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein R¹ is C₁₋₆alkyl.
 3. The compound of claim 1 wherein R¹ ismethyl.
 4. The compound of claim 1 wherein R¹ is ethyl.
 5. The compoundof claim 1 wherein R² is:R⁴—S(O)₂—NR⁵— and wherein R⁴ is selected from the group consisting of:(1) C₁₋₆alkyl, (2) phenyl, and (3) benzyl; R⁵ is selected from the groupconsisting of: (1) C₁₋₆alkyl, (2) phenyl, (3) benzyl, and (4) hydrogen.6. The compound of claim 1 wherein R³ is:

and wherein R⁵ is methyl, R^(6a) is H or F, R^(6b) and R^(6c) arehydrogen.
 7. The compound of claim 1 wherein R³ is:


8. The compound of claim 1 wherein R⁹ is hydrogen.
 9. The compound ofclaim 1 wherein R¹⁰ is C₁₋₆alkyl.
 10. The compound of claim 1 whereinR¹⁰ is iso-butyl.
 11. A compound which is selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound of claim 1 and a pharmaceutically acceptable carrier.